J-ethylenedioxy



United States Patent Ofifice 3,127,397 Patented Mar. 31, 1964 3,127,3973-ETHYLENEDKOXY-I7B=BENZYLOXYSTEROIDS Eugene L. Woroch, Itasca, Ill.,assignor to Abbott Laboratories, North Chicago, Ill., a corporation ofIllinois No Drawing. Filed Sept. 10, 1962, Ser. No. 222,633 3 Claims.(Cl. 260--23.55)

The present invention is concerned with steroid others; moreparticularly, it is concerned with the 17-benzyl ethers of steroids ofthe androstane and estrane series carrying in the 3-position a ketogroup or an ethylenedioxy group.

The new steroids can be expressed by the formula AIB wherein the A/Brings have a configuration selected from and CHzO m I J CHzO wherein Ris oxygen or ethylenedioxy and wherein R is hydrogen or methyl.

The new compounds of the present invention are useful as hormonalagents; they have androgenic activity.

The new 17-steroid others are prepared by a very simple processconsisting essentially in refluxing a saturated or S-unsaturated3-ethylenedioxy-17-hydroxysteroid with an alkali metal in awater-immiscible, inert solvent, converting the formed alkali metal saltto the corresponding benzyl ether by treating it with benzyl halide and,if desired, hydrolyzing the ketal group in the 3-position to thecarbonyl group. In the case of a A -3-ethylenedioxysteroid, the initialdouble bond in the 5-position remains at 56 While, after hydrolysis ofthe ethylenedioxy group to the corresponding keto group, the double bondshifts to the 4-5 position.

The present invention is more clearly described by reference to thefollowing examples which are given here as illustrations only and arenot meant to limit the invention in any respect.

EXAMPLE 1 3 -Ethylenedi0xy-1 713-3enzyloxyarzdrost-S-Ene A threeneckedflask is charged with 3.0 grams of 3- ethylenedioxyandrost-S-en-17,8-01,300 ml. of dry, thio phene-free benzene, and 2.4 grams of potassiummetal. The mixture is refluxed and stirred vigorously for 3 hours. Theresulting suspension is treated with 12 ml. of benzyl bromide andstirred under reflux for 17 hours. The excess potassium is decomposed bythe addition of 25 ml. of tertiary butyl alcohol. The solution is thenpoured into water and the organic layer is separated and washed withwater. A few drops of pyridine are added to the washed, organic phasewhich is then evaporated to dryness under vacuum. The sticky solidobtained is purified by dissolving it in ethanol, slowly evaporating thesolvent and replacing the evaporating ethanol with benzene. Uponcooling, 2.88 grams of 3-ethylenedioxy-17B-benzoyloxyandrost-S-enemelting at 197200 C. is obtained. An analytical sample obtained byrecrystallization from benzene/petroleum ether is obtained in prismsmelting at 207-208 C. in an evacuated melting-point tube; it analyzes79.71% C and 9.0% H, which is in agreement with the calculated valuesfor C H O EXAMPLE 2 1 7 B-Benzyloxyandrost-4-En-3-One A suspension of1.25 grams of 3-ethylenedioxy-17flbenzyloxyandrost-S-ene in 125 ml. ofmethanol, 20 ml. of benzene, and 5 ml. of 10% aqueous hydrochloric acidis warmed until a clear solution is formed. After standing overnight atroom temperature, the solution is concentrated in vacuo and the residueis diluted with water. The crystals thus obtained are filtered, washedwith water, and dried, yielding 1.07 grams of 17/8-benzyloxyandrost-4-en-3-one, melting at 12l-126 C. An analytical sample obtained asprisms from ether/petroleum ether by the above-describedsolvent-evaporation/replacement method, melts at 126-1285 C. andanalyzes 82.39% C and 8.94% H which is in agreement with the calculatedvalues for C H O EXAMLE 3 3-Ethylenedioxy-1 7 fi-Benzyloxyestrene Byreplacing the 3-ethy1enedioxyandrost-S-en-l7fl-ol of Example 1 with3-ethlylenedioxyestren-175-01 which contains a double-bond connecting tothe 5-position, and otherwise proceeding exactly as described in Example1, a mixture of A and A -ethylenedioxy-l7,8-benzyloxy-estrene isobtained, having an empirical formula of C H O The3-ethylenedioxy-l7fi-benzyloxyestr-5(6)- ene is separated from3-ethylenedioxy-17B-benzyloxyestr- 5(10)-ene by known chromatographicmethods.

EXAMPLE 4 1 7 fi-Be'nzyloxyestr-4-En-3-One By following the proceduredescribed in Example 2 but replacing3-ethylenedioxy-17,8-benzyloxyandrost-S-ene with either one of the3-ethylenedioxy-17,8-lbenzyloxyestrenes of Example 3 or their mixture,17 3-benzyloxyestr-4-en-3-one is obtained, having an empirical formulaof C H O In analogy with the above examples, the corresponding saturatedcompounds can also be prepared in the same manner, starting with3-ethylenedioxyandrostan-175-01 or 3-ethylenedioxyestran-173-01,respectively. The compounds obtained thereby are 3-ethylenedioxy-173-benzyloxyandrostane (C H O which hydrolyzes to 17/3-benzyloxyandrostan-3-one (C H O- and3-ethylenedioxy-17fl-benzyloxyestrane (C H O which hydrolyzes tol7fl-benzyloxyestran-3-one (C H O In the process of preparing the newsteroid others, the corresponding 17-hydroxysteroid is first convertedto the alkali metal salt, preferably the lithium, potassium or sodiumsalt. This reaction is carried out at a temperature between 40 and C. inthe presence of an inert,

water-immiscible solvent. The term inert is meant to express that thesolvent does not enter any reaction with either component of thereaction mixture, with the resulting steroid ether to be formed, or withthe benzyl halide with which this salt is to be reacted. Among thesesolvents are benzene, toluene, xylenes, petroleum ether, and otherhigh-boiling hydrocarbons, etc.

The benzyl halide used in the present process is chosen from benzylchloride or benzyl bromide. The reaction with this benzyl halide ispreferably carried out at a temperature between 40 and 120 C. for aperiod exceeding 3 hours. It is to be noted that any excess alkali metalwhich may still be in suspension at this point of the reaction can bedestroyed after the steroid ether is formed by adding to the reactionmixture an alcohol, e.g., tertiary butyl alcohol or similar low-boilingalcohols. Since the initial reaction mixture is in a water-immisciblesolvent, pouring the formed mixture containing the benzyl ether intowater produces two layers. The steroid benzyl ether can be isolated fromthe organic layer by evaporation of the solvent or by adding a secondliquid, miscible, organic medium in which the ether is insoluble.

Others may practice the invention in any of the tru merous ways whichWill be apparent to one skilled in the art by the present disclosure.All such practice of the invention shall be considered a part hereofprovided it falls Within the scope of the appended claims.

I claim:

1. 17fi-benzyloxy-3-ethylenedioxyandrost-S-ene.

2. 17fi-benzyloxy-3-ethylenedioxyestr-5 10)-ene.

3. 17,8-benzyloxy-3-ethylenedioxyestr-5 (6)-ene.

References Cited in the file of this patent UNITED STATES PATENTSDjerassi et al Mar. 29, 1955 Colton Mar. 27, 1956 OTHER REFERENCES

1. 17B-BENZYLOXY-3-ETHYLENEDIOXYANDROST-5-ENE. 